Reviews

Low-grade non-Hodgkin’s lymphoma (NHL) is an indolent form of the disease with a generally slow course of progression. Although still usually incurable, low-grade disease has shown responsiveness to some of the newer chemotherapeutic and nonchemotherapeutic treatment options. However, since cure remains elusive, and since many patients with low-grade NHL may have few or even no symptoms initially, the decision about whether or not to initiate treatment logically must include quality-of-life (QOL) issues. This paper summarizes clinical and diagnostic characteristics of low-grade NHL that have some bearing on QOL considerations. Adverse effects of the more common treatment approaches are discussed according to their QOL implications, illustrating the relevance of QOL to the clinical management of low-grade disease. Finally, data from an ongoing study using the Functional Assessment of Cancer Therapy (FACT) measurement system are presented. These data offer a basis for comparing the QOL of patients with NHL to that of individuals with other solid tumors, and also illustrate the effects of chemotherapy on QOL.[ONCOLOGY 12(5): 697-717, 1998]

In 1997, an estimated 54,000 people in the United States were diagnosed with non-Hodgkin’s lymphoma (NHL).[1] This disease thus accounted for nearly 4% of cancer incidence overall.[1] In the same year (1997), almost 24,000 people died of the disease.[1]

The subclassification of low-grade NHL constitutes approximately 25% of all cases.[2] Incidence of low-grade disease is higher in people between the ages of 35 and 64 years (37%) than in those under age 35 (16%).[3] Ironically termed the “favorable” or indolent form of NHL due to a natural history characterized by slow disease progression and a relatively long duration of survival (7 to 10 years)[4] when compared to intermediate- and high-grade disease, low-grade NHL is still regarded as essentially incurable.[5,6]

The addition of new treatment options, a better understanding of factors that predict response, and the introduction of new nonchemotherapeutic therapies have improved the clinical management of low-grade NHL. These improvements have not yet produced a significant increase in cure rate, however.[7-9] For this reason, and because life-extending treatments produce toxicity and added cost, quality of life (QOL) emerges as a very relevant consideration when judging therapeutic benefit.

The course of progressive low-grade NHL is typified by sequential remissions and relapses, disease dissemination, and eventual resistance to current treatment approaches.[6] Also, since patients often opt for alternative treatments at times of relapse, they are likely to endure acute and chronic treatment toxicity, as well as psychosocial sequelae associated with chronic, life-threatening disease.

In summary, given that the disease produces symptoms, the chance for cure is low, and available treatments have a questionable impact on survival and known toxicity (or cost), QOL may be the most important clinical management concern. To date, however, there has been a paucity of relevant literature and research on the quality of life of patients with low-grade lymphoma, and no published randomized clinical trial has included QOL evaluation as an outcome. The need for reliable, valid measures of the physical, functional, emotional, and social impact of lymphoma is apparent. Although questionnaires that measure general QOL are available,[10-12] there is no lymphoma-specific QOL questionnaire or subscale that addresses the particular symptoms or concerns of patients with lymphoma or the effects of lymphoma treatments on life quality. Treatment decision-making (by both patient and physician) and practice guidelines would be enhanced by the ability to balance QOL consequences against the known benefits and drawbacks of established and investigational treatments, such as extension of survival time, durability of remission, toxicity of treatment, and effectiveness of palliation.

This paper will summarize the clinical characteristics of low-grade NHL, including classification, staging, and symptoms, as well as the predictors of treatment response. Adverse effects of the most common treatments and their QOL implications will also be discussed, in an attempt to illustrate the high degree of relevance of QOL considerations to clinical management. In addition, the psychosocial sequelae of NHL will be reviewed. Finally, data derived from a commonly used questionnaire, the Functional Assessment of Cancer Therapy (FACT) measurement system,[10] will be presented. These data were used to compare the QOL of patients with NHL to a matched sample of patients with mixed cancer types and a smaller sample of patients with Hodgkin’s disease; the QOL of NHL patients according to treatment status (on vs off chemotherapy) were also compared.

Clinical Characteristics

Classification and StagingNon-Hodgkin’s lymphomas comprise a wide range of malignancies that originate in the lymphoid system. They differ according to their pathologic and immunologic characteristics and their prognostic classification.[3,5,6] Efforts have been made to create a taxonomy that effectively groups all lymphomas into distinct categories according to their morphology, course, and outcome. Due to the variability of lymphomas, however, development of a pure classification system still remains challenging.[6]

At present, NHLs are commonly classified by the International Working Formulation, established in 1982 by a special task force of the National Cancer Institute to consolidate lymphomas by clinically useful criteria so as to predict biological behavior, curability, and survival.[13] Another classification system, the revised European-American classification of lymphoid neoplasms (REAL) has been proposed but is not universally accepted.[14] Precise diagnostic evaluation of the histologic subtype and classification have become critical for appropriate management of the disease.[6]

The International Working Formulation defines three general categories of lymphomas—low grade, intermediate grade, and high grade—which are differentiated most notably by their aggressiveness or “malignant potential.”[5] Low-grade lymphomas include small lymphocytic; follicular, small cleaved cell; and follicular, mixed, small cleaved and large cell subtypes, which are indolent by nature and initially responsive to a variety of treatments but eventually prove nonresponsive.[6]

An unusual increase in the incidence of NHL since the 1970s,[5] combined with little improvement in relative survival rates, continues to challenge the medical community,[1] despite the availability of diverse treatment options. Risk factors associated with low-grade lymphomas include increasing age, male gender, exposure to chemotherapy and radiation, and chronic immunosuppression.[3,5] Of particular importance to QOL are practice guidelines based on poor prognostic factors, such as age.

Repeat assessments are necessary to determine response to treatment and guide therapeutic decisions. Chronic invasive assessments in patients with hematologic malignancies cause discomfort and are associated with heightened anxiety, especially at follow-up visits, where fear of recurrence may be confirmed.[16]

SymptomsDisease symptoms include both common lymphoma symptoms that are indicative of active disease and specific symptoms highly influenced by the location(s) and extent of disease dissemination.[5] The majority of patients present initially with asymptomatic adenopathy (lymph node swelling) and may have active disease without symptoms for up to 3 years after diagnosis, making early treatment (for some) optional.[17] The indolent nature of the low-grade subtypes may also allow some patients to live a relatively prolonged symptom-free and active life until the disease progresses.

Nonspecific lymphoma symptoms, commonly referred to as B symptoms, include fatigue, fever, weight loss, and drenching night sweats. These symptoms are prognostically unfavorable and therefore are often an indication for treatment.[18] Other relevant symptoms include pain and cosmetic problems due to enlarged lymph nodes.

Independent of prognostic differences, treatment of symptomatic disease is more easily justifiable than treatment of asymptomatic disease, on QOL grounds. This will be addressed below.

Site-specific involvement can be limited or widespread, can occur anywhere in the lymphatic system (eg, lymph nodes, spleen, and bone marrow), and can spread to one or more extralymphatic organs (eg, stomach, intestine, bone, skin, oral cavity, and pharynx).[3,5] The presence of bulky masses causes discomfort and often pain.

Other symptoms vary and may include abdominal pain, ulcers, or bleeding if the gastrointestinal (GI) tract is involved.[5] If there is throat or sinus involvement, head and neck discomfort, throat pain, or swallowing difficulty can occur.[5] Patients with neurologic or musculoskeletal system involvement may experience neurologic and musculoskeletal pain and muscle weakness. With bone marrow involvement, weakened immunity or chronic infections can develop.[3]

In short, the range of possible symptoms and functional problems associated with low-grade NHL is diverse, and depends on the site and degree of involvement. Progressive disease dissemination to additional sites places patients at increased risk for new symptoms and problems, which are often unpredictable, although manageable with palliative therapies.